Multi-Ancestry Genome-Wide Association Study of Lipid Levels Incorporating Gene-Alcohol Interactions

de Vries, Paul S.; Brown, Michael R.; Bentley, Amy R.; Sung, Yun J.; Winkler, Thomas W.; Ntalla, Ioanna; Schwander, Karen; Kraja, Aldi T.; Guo, Xiuqing; Franceschini, Nora; Cheng, Ching-Yu; Sim, Xueling; Vojinovic, Dina; Huffman, Jennifer E.; Musani, Solomon K.; Li, Changwei; Feitosa, Mary F.; Richard, Melissa A.; Noordam, Raymond; Aschard, Hugues; Bartz, Traci M.; Bielak, Lawrence F.; Deng, Xuan; Dorajoo, Rajkumar; Lohman, Kurt K.; Manning, Alisa K.; Rankinen, Tuomo; Smith, Albert V.; Tajuddin, Salman M.; Evangelou, Evangelos; Graff, Mariaelisa; Alver, Maris; Boissel, Mathilde; Chai, Jin Fang; Chen, Xu; Divers, Jasmin; Gandin, Ilaria; Gao, Chuan; Goel, Anuj; Hagemeijer, Yanick; Harris, Sarah E.; Hartwig, Fernando P.; He, Meian; Horimoto, Andrea R. V. R.; Hsu, Fang-Chi; Jackson, Anne U.; Kasturiratne, Anuradhani; Komulainen, Pirjo; Kuhnel, Brigitte; Laguzzi, Federica; Lee, Joseph H.; Luan, Jian'an; Lyytikainen, Leo-Pekka; Matoba, Nana; Nolte, Ilja M.; Pietzner, Maik; Riaz, Muhammad; Said, M. Abdullah; Scott, Robert A.; Sofer, Tamar; Stancakova, Alena; Takeuchi, Fumihiko; Tayo, Bamidele O.; van der Most, Peter J.; Varga, Tibor V.; Wang, Yajuan; Ware, Erin B.; Wen, Wanqing; Yanek, Lisa R.; Zhang, Weihua; Zhao, Jing Hua; Afaq, Saima; Amin, Najaf; Amini, Marzyeh; Arking, Dan E.; Aung, Tin; Ballantyne, Christie; Boerwinkle, Eric A.; Broeckel, Ulrich; Campbell, Archie; Canouil, Mickael; Charumathi, Sabanayagam; Chen, Yii-Der Ida; Connell, John M.; de Faire, Ulf; de Las Fuentes, Lisa; de Mutsert, Renee; de Silva, H. Janaka; Ding, Jingzhong; Dominiczak, Anna F.; Duan, Qing; Eaton, Charles B.; Eppinga, Ruben N.; Faul, Jessica D.; Fisher, Virginia; Forrester, Terrence; Franco, Oscar H.; Friedlander, Yechiel; Ghanbari, Mohsen; Giulianini, Franco; Grabe, Hans J.; Grove, Megan L.; Gu, C. Charles; Harris, Tamara B.; Heikkinen, Sami; Heng, Chew-Kiat; Hirata, Makoto; Hixson, James E.; Howard, Barbara V.; Ikram, M. Arfan; InterAct Consortium, the; Jacobs, David R., Jr.; Johnson, Craig; Jonas, Jost Bruno; Kammerer, Candace M.; Katsuya, Tomohiro; Khor, Chiea Chuen; Kilpelainen, Tuomas O.; Koh, Woon-Puay; Koistinen, Heikki A.; Kolcic, Ivana; Kooperberg, Charles L.; Krieger, Jose E.; Kritchevsky, Steve B.; Kubo, Michiaki; Kuusisto, Johanna; Lakka, Timo A.; Langefeld, Carl D.; Langenberg, Claudia; Launer, Lenore J.; Lehne, Benjamin; Lemaitre, Rozenn N.; Li, Yize; Liang, Jingjing; Liu, Jianjun; Liu, Kiang; Loh, Marie; Louie, Tin; Magi, Reedik; Manichaikul, Ani W.; McKenzie, Colin A.; Meitinger, Thomas; Metspalu, Andres; Milaneschi, Yuri; Milani, Lili; Mohlke, Karen L.; Mosley, Thomas H., Jr.; Mukamal, Kenneth J.; Nalls, Mike A.; Nauck, Matthias; Nelson, Christopher P.; Sotoodehnia, Nona; O'Connell, Jeff R.; Palmer, Nicholette D.; Pazoki, Raha; Pedersen, Nancy L.; Peters, Annette; Peyser, Patricia A.; Polasek, Ozren; Poulter, Neil; Raffel, Leslie J.; Raitakari, Olli T.; Reiner, Alex P.; Rice, Treva K.; Rich, Stephen S.; Robino, Antonietta; Robinson, Jennifer G.; Rose, Lynda M.; Rudan, Igor; Schmidt, Carsten O.; Schreiner, Pamela J.; Scott, William R.; Sever, Peter; Shi, Yuan; Sidney, Stephen; Sims, Mario; Smith, Blair H.; Smith, Jennifer A.; Snieder, Harold; Starr, John M.; Strauch, Konstantin; Tan, Nicholas; Taylor, Kent D.; Teo, Yik Ying; Tham, Yih Chung; Uitterlinden, Andre G.; van Heemst, Diana; Vuckovic, Dragana; Waldenberger, Melanie; Wang, Lihua; Wang, Yujie; Wang, Zhe; Wei, Wen Bin; Williams, Christine; Wilson, Gregory, Sr.; Wojczynski, Mary K.; Yao, Jie; Yu, Bing; Yu, Caizheng; Yuan, Jian-Min; Zhao, Wei; Zonderman, Alan B.; Becker, Diane M.; Boehnke, Michael; Bowden, Donald W.; Chambers, John C.; Deary, Ian J.; Esko, Tonu; Farrall, Martin; Franks, Paul W.; Freedman, Barry I.; Froguel, Philippe; Gasparini, Paolo; Gieger, Christian; Horta, Bernardo L.; Kamatani, Yoichiro; Kato, Norihiro; Kooner, Jaspal S.; Laakso, Markku; Leander, Karin; Lehtimaki, Terho; Lifelines Cohort, Groningen, The Netherlands (Lifelines Cohort Study); Magnusson, Patrik K. E.; Penninx, Brenda; Pereira, Alexandre C.; Rauramaa, Rainer; Samani, Nilesh J.; Scott, James; Shu, Xiao-Ou; van der Harst, Pim; Wagenknecht, Lynne E.; Wang, Ya Xing; Wareham, Nicholas J.; Watkins, Hugh; Weir, David R.; Wickremasinghe, Ananda R.; Zheng, Wei; Elliott, Paul; North, Kari E.; Bouchard, Claude; Evans, Michele K.; Gudnason, Vilmundur; Liu, Ching-Ti; Liu, Yongmei; Psaty, Bruce M.; Ridker, Paul M.; van Dam, Rob M.; Kardia, Sharon L. R.; Zhu, Xiaofeng; Rotimi, Charles N.; Mook-Kanamori, Dennis O.; Fornage, Myriam; Kelly, Tanika N.; Fox, Ervin R.; Hayward, Caroline; van Duijn, Cornelia M.; Tai, E. Shyong; Wong, Tien Yin; Liu, Jingmin; Rotter, Jerome I.; Gauderman, W. James; Province, Michael A.; Munroe, Patricia B.; Rice, Kenneth; Chasman, Daniel I.; Cupples, L. Adrienne; Rao, Dabeeru C.; & Morrison, Alanna C. (Forthcoming). Multi-Ancestry Genome-Wide Association Study of Lipid Levels Incorporating Gene-Alcohol Interactions. American Journal of Epidemiology.

de Vries, Paul S.; Brown, Michael R.; Bentley, Amy R.; Sung, Yun J.; Winkler, Thomas W.; Ntalla, Ioanna; Schwander, Karen; Kraja, Aldi T.; Guo, Xiuqing; Franceschini, Nora; Cheng, Ching-Yu; Sim, Xueling; Vojinovic, Dina; Huffman, Jennifer E.; Musani, Solomon K.; Li, Changwei; Feitosa, Mary F.; Richard, Melissa A.; Noordam, Raymond; Aschard, Hugues; Bartz, Traci M.; Bielak, Lawrence F.; Deng, Xuan; Dorajoo, Rajkumar; Lohman, Kurt K.; Manning, Alisa K.; Rankinen, Tuomo; Smith, Albert V.; Tajuddin, Salman M.; Evangelou, Evangelos; Graff, Mariaelisa; Alver, Maris; Boissel, Mathilde; Chai, Jin Fang; Chen, Xu; Divers, Jasmin; Gandin, Ilaria; Gao, Chuan; Goel, Anuj; Hagemeijer, Yanick; Harris, Sarah E.; Hartwig, Fernando P.; He, Meian; Horimoto, Andrea R. V. R.; Hsu, Fang-Chi; Jackson, Anne U.; Kasturiratne, Anuradhani; Komulainen, Pirjo; Kuhnel, Brigitte; Laguzzi, Federica; Lee, Joseph H.; Luan, Jian'an; Lyytikainen, Leo-Pekka; Matoba, Nana; Nolte, Ilja M.; Pietzner, Maik; Riaz, Muhammad; Said, M. Abdullah; Scott, Robert A.; Sofer, Tamar; Stancakova, Alena; Takeuchi, Fumihiko; Tayo, Bamidele O.; van der Most, Peter J.; Varga, Tibor V.; Wang, Yajuan; Ware, Erin B.; Wen, Wanqing; Yanek, Lisa R.; Zhang, Weihua; Zhao, Jing Hua; Afaq, Saima; Amin, Najaf; Amini, Marzyeh; Arking, Dan E.; Aung, Tin; Ballantyne, Christie; Boerwinkle, Eric A.; Broeckel, Ulrich; Campbell, Archie; Canouil, Mickael; Charumathi, Sabanayagam; Chen, Yii-Der Ida; Connell, John M.; de Faire, Ulf; de Las Fuentes, Lisa; de Mutsert, Renee; de Silva, H. Janaka; Ding, Jingzhong; Dominiczak, Anna F.; Duan, Qing; Eaton, Charles B.; Eppinga, Ruben N.; Faul, Jessica D.; Fisher, Virginia; Forrester, Terrence; Franco, Oscar H.; Friedlander, Yechiel; Ghanbari, Mohsen; Giulianini, Franco; Grabe, Hans J.; Grove, Megan L.; Gu, C. Charles; Harris, Tamara B.; Heikkinen, Sami; Heng, Chew-Kiat; Hirata, Makoto; Hixson, James E.; Howard, Barbara V.; Ikram, M. Arfan; InterAct Consortium, the; Jacobs, David R., Jr.; Johnson, Craig; Jonas, Jost Bruno; Kammerer, Candace M.; Katsuya, Tomohiro; Khor, Chiea Chuen; Kilpelainen, Tuomas O.; Koh, Woon-Puay; Koistinen, Heikki A.; Kolcic, Ivana; Kooperberg, Charles L.; Krieger, Jose E.; Kritchevsky, Steve B.; Kubo, Michiaki; Kuusisto, Johanna; Lakka, Timo A.; Langefeld, Carl D.; Langenberg, Claudia; Launer, Lenore J.; Lehne, Benjamin; Lemaitre, Rozenn N.; Li, Yize; Liang, Jingjing; Liu, Jianjun; Liu, Kiang; Loh, Marie; Louie, Tin; Magi, Reedik; Manichaikul, Ani W.; McKenzie, Colin A.; Meitinger, Thomas; Metspalu, Andres; Milaneschi, Yuri; Milani, Lili; Mohlke, Karen L.; Mosley, Thomas H., Jr.; Mukamal, Kenneth J.; Nalls, Mike A.; Nauck, Matthias; Nelson, Christopher P.; Sotoodehnia, Nona; O'Connell, Jeff R.; Palmer, Nicholette D.; Pazoki, Raha; Pedersen, Nancy L.; Peters, Annette; Peyser, Patricia A.; Polasek, Ozren; Poulter, Neil; Raffel, Leslie J.; Raitakari, Olli T.; Reiner, Alex P.; Rice, Treva K.; Rich, Stephen S.; Robino, Antonietta; Robinson, Jennifer G.; Rose, Lynda M.; Rudan, Igor; Schmidt, Carsten O.; Schreiner, Pamela J.; Scott, William R.; Sever, Peter; Shi, Yuan; Sidney, Stephen; Sims, Mario; Smith, Blair H.; Smith, Jennifer A.; Snieder, Harold; Starr, John M.; Strauch, Konstantin; Tan, Nicholas; Taylor, Kent D.; Teo, Yik Ying; Tham, Yih Chung; Uitterlinden, Andre G.; van Heemst, Diana; Vuckovic, Dragana; Waldenberger, Melanie; Wang, Lihua; Wang, Yujie; Wang, Zhe; Wei, Wen Bin; Williams, Christine; Wilson, Gregory, Sr.; Wojczynski, Mary K.; Yao, Jie; Yu, Bing; Yu, Caizheng; Yuan, Jian-Min; Zhao, Wei; Zonderman, Alan B.; Becker, Diane M.; Boehnke, Michael; Bowden, Donald W.; Chambers, John C.; Deary, Ian J.; Esko, Tonu; Farrall, Martin; Franks, Paul W.; Freedman, Barry I.; Froguel, Philippe; Gasparini, Paolo; Gieger, Christian; Horta, Bernardo L.; Kamatani, Yoichiro; Kato, Norihiro; Kooner, Jaspal S.; Laakso, Markku; Leander, Karin; Lehtimaki, Terho; Lifelines Cohort, Groningen, The Netherlands (Lifelines Cohort Study); Magnusson, Patrik K. E.; Penninx, Brenda; Pereira, Alexandre C.; Rauramaa, Rainer; Samani, Nilesh J.; Scott, James; Shu, Xiao-Ou; van der Harst, Pim; Wagenknecht, Lynne E.; Wang, Ya Xing; Wareham, Nicholas J.; Watkins, Hugh; Weir, David R.; Wickremasinghe, Ananda R.; Zheng, Wei; Elliott, Paul; North, Kari E.; Bouchard, Claude; Evans, Michele K.; Gudnason, Vilmundur; Liu, Ching-Ti; Liu, Yongmei; Psaty, Bruce M.; Ridker, Paul M.; van Dam, Rob M.; Kardia, Sharon L. R.; Zhu, Xiaofeng; Rotimi, Charles N.; Mook-Kanamori, Dennis O.; Fornage, Myriam; Kelly, Tanika N.; Fox, Ervin R.; Hayward, Caroline; van Duijn, Cornelia M.; Tai, E. Shyong; Wong, Tien Yin; Liu, Jingmin; Rotter, Jerome I.; Gauderman, W. James; Province, Michael A.; Munroe, Patricia B.; Rice, Kenneth; Chasman, Daniel I.; Cupples, L. Adrienne; Rao, Dabeeru C.; & Morrison, Alanna C. (Forthcoming). Multi-Ancestry Genome-Wide Association Study of Lipid Levels Incorporating Gene-Alcohol Interactions. American Journal of Epidemiology.

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An individual's lipid profile is influenced by genetic variants and alcohol consumption, but the contribution of interactions between these exposures has not been studied. We therefore incorporated gene-alcohol interactions into a multi-ancestry genome-wide association study of levels of high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and triglycerides. We included 45 studies in Stage 1 (genome-wide discovery) and 66 studies in Stage 2 (focused follow-up), for a total of 394,584 individuals from five ancestry groups. Genetic main and interaction effects were jointly assessed by a 2 degrees of freedom (DF) test, and a 1 DF test was used to assess the interaction effects alone. Variants at 495 loci were at least suggestively associated (P < 1 x 10-6) with lipid levels in Stage 1 and were evaluated in Stage 2, followed by combined analyses of Stage 1 and Stage 2. In the combined analysis of Stage 1 and Stage 2, 147 independent loci were associated with lipid levels at P < 5 x 10-8 using 2 DF tests, of which 18 were novel. No genome-wide significant associations were found testing the interaction effect alone. The novel loci included several genes (PCSK5, VEGFB, and A1CF) with a putative role in lipid metabolism based on existing evidence from cellular and experimental models.




JOUR



de Vries, Paul S.
Brown, Michael R.
Bentley, Amy R.
Sung, Yun J.
Winkler, Thomas W.
Ntalla, Ioanna
Schwander, Karen
Kraja, Aldi T.
Guo, Xiuqing
Franceschini, Nora
Cheng, Ching-Yu
Sim, Xueling
Vojinovic, Dina
Huffman, Jennifer E.
Musani, Solomon K.
Li, Changwei
Feitosa, Mary F.
Richard, Melissa A.
Noordam, Raymond
Aschard, Hugues
Bartz, Traci M.
Bielak, Lawrence F.
Deng, Xuan
Dorajoo, Rajkumar
Lohman, Kurt K.
Manning, Alisa K.
Rankinen, Tuomo
Smith, Albert V.
Tajuddin, Salman M.
Evangelou, Evangelos
Graff, Mariaelisa
Alver, Maris
Boissel, Mathilde
Chai, Jin Fang
Chen, Xu
Divers, Jasmin
Gandin, Ilaria
Gao, Chuan
Goel, Anuj
Hagemeijer, Yanick
Harris, Sarah E.
Hartwig, Fernando P.
He, Meian
Horimoto, Andrea R. V. R.
Hsu, Fang-Chi
Jackson, Anne U.
Kasturiratne, Anuradhani
Komulainen, Pirjo
Kuhnel, Brigitte
Laguzzi, Federica
Lee, Joseph H.
Luan, Jian'an
Lyytikainen, Leo-Pekka
Matoba, Nana
Nolte, Ilja M.
Pietzner, Maik
Riaz, Muhammad
Said, M. Abdullah
Scott, Robert A.
Sofer, Tamar
Stancakova, Alena
Takeuchi, Fumihiko
Tayo, Bamidele O.
van der Most, Peter J.
Varga, Tibor V.
Wang, Yajuan
Ware, Erin B.
Wen, Wanqing
Yanek, Lisa R.
Zhang, Weihua
Zhao, Jing Hua
Afaq, Saima
Amin, Najaf
Amini, Marzyeh
Arking, Dan E.
Aung, Tin
Ballantyne, Christie
Boerwinkle, Eric A.
Broeckel, Ulrich
Campbell, Archie
Canouil, Mickael
Charumathi, Sabanayagam
Chen, Yii-Der Ida
Connell, John M.
de Faire, Ulf
de Las Fuentes, Lisa
de Mutsert, Renee
de Silva, H. Janaka
Ding, Jingzhong
Dominiczak, Anna F.
Duan, Qing
Eaton, Charles B.
Eppinga, Ruben N.
Faul, Jessica D.
Fisher, Virginia
Forrester, Terrence
Franco, Oscar H.
Friedlander, Yechiel
Ghanbari, Mohsen
Giulianini, Franco
Grabe, Hans J.
Grove, Megan L.
Gu, C. Charles
Harris, Tamara B.
Heikkinen, Sami
Heng, Chew-Kiat
Hirata, Makoto
Hixson, James E.
Howard, Barbara V.
Ikram, M. Arfan
InterAct Consortium, the
Jacobs, David R., Jr.
Johnson, Craig
Jonas, Jost Bruno
Kammerer, Candace M.
Katsuya, Tomohiro
Khor, Chiea Chuen
Kilpelainen, Tuomas O.
Koh, Woon-Puay
Koistinen, Heikki A.
Kolcic, Ivana
Kooperberg, Charles L.
Krieger, Jose E.
Kritchevsky, Steve B.
Kubo, Michiaki
Kuusisto, Johanna
Lakka, Timo A.
Langefeld, Carl D.
Langenberg, Claudia
Launer, Lenore J.
Lehne, Benjamin
Lemaitre, Rozenn N.
Li, Yize
Liang, Jingjing
Liu, Jianjun
Liu, Kiang
Loh, Marie
Louie, Tin
Magi, Reedik
Manichaikul, Ani W.
McKenzie, Colin A.
Meitinger, Thomas
Metspalu, Andres
Milaneschi, Yuri
Milani, Lili
Mohlke, Karen L.
Mosley, Thomas H., Jr.
Mukamal, Kenneth J.
Nalls, Mike A.
Nauck, Matthias
Nelson, Christopher P.
Sotoodehnia, Nona
O'Connell, Jeff R.
Palmer, Nicholette D.
Pazoki, Raha
Pedersen, Nancy L.
Peters, Annette
Peyser, Patricia A.
Polasek, Ozren
Poulter, Neil
Raffel, Leslie J.
Raitakari, Olli T.
Reiner, Alex P.
Rice, Treva K.
Rich, Stephen S.
Robino, Antonietta
Robinson, Jennifer G.
Rose, Lynda M.
Rudan, Igor
Schmidt, Carsten O.
Schreiner, Pamela J.
Scott, William R.
Sever, Peter
Shi, Yuan
Sidney, Stephen
Sims, Mario
Smith, Blair H.
Smith, Jennifer A.
Snieder, Harold
Starr, John M.
Strauch, Konstantin
Tan, Nicholas
Taylor, Kent D.
Teo, Yik Ying
Tham, Yih Chung
Uitterlinden, Andre G.
van Heemst, Diana
Vuckovic, Dragana
Waldenberger, Melanie
Wang, Lihua
Wang, Yujie
Wang, Zhe
Wei, Wen Bin
Williams, Christine
Wilson, Gregory, Sr.
Wojczynski, Mary K.
Yao, Jie
Yu, Bing
Yu, Caizheng
Yuan, Jian-Min
Zhao, Wei
Zonderman, Alan B.
Becker, Diane M.
Boehnke, Michael
Bowden, Donald W.
Chambers, John C.
Deary, Ian J.
Esko, Tonu
Farrall, Martin
Franks, Paul W.
Freedman, Barry I.
Froguel, Philippe
Gasparini, Paolo
Gieger, Christian
Horta, Bernardo L.
Kamatani, Yoichiro
Kato, Norihiro
Kooner, Jaspal S.
Laakso, Markku
Leander, Karin
Lehtimaki, Terho
Lifelines Cohort, Groningen, The Netherlands (Lifelines Cohort Study)
Magnusson, Patrik K. E.
Penninx, Brenda
Pereira, Alexandre C.
Rauramaa, Rainer
Samani, Nilesh J.
Scott, James
Shu, Xiao-Ou
van der Harst, Pim
Wagenknecht, Lynne E.
Wang, Ya Xing
Wareham, Nicholas J.
Watkins, Hugh
Weir, David R.
Wickremasinghe, Ananda R.
Zheng, Wei
Elliott, Paul
North, Kari E.
Bouchard, Claude
Evans, Michele K.
Gudnason, Vilmundur
Liu, Ching-Ti
Liu, Yongmei
Psaty, Bruce M.
Ridker, Paul M.
van Dam, Rob M.
Kardia, Sharon L. R.
Zhu, Xiaofeng
Rotimi, Charles N.
Mook-Kanamori, Dennis O.
Fornage, Myriam
Kelly, Tanika N.
Fox, Ervin R.
Hayward, Caroline
van Duijn, Cornelia M.
Tai, E. Shyong
Wong, Tien Yin
Liu, Jingmin
Rotter, Jerome I.
Gauderman, W. James
Province, Michael A.
Munroe, Patricia B.
Rice, Kenneth
Chasman, Daniel I.
Cupples, L. Adrienne
Rao, Dabeeru C.
Morrison, Alanna C.



Forthcoming


American Journal of Epidemiology













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